Abeysinghe, Rajeewa Dhammika; (1995) The use of metal chelators in radiolabelling of platelets and their effects on cell function. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Indium labelling of blood platelets is a diagnostic technique often used in imaging studies and kinetic studies. Conventional platelet labelling techniques have principally used either oxine or tropolone as labelling agents but, unfortunately, they have many reported toxicities. In order to identify new compounds which label cells with a high efficiency but with low toxicity, chelators from the hydroxypyridinone and hydroxypyranone families have been systematically investigated as potential platelet labelling agents with radioindium. The optimal labelling conditions have been investigated and compared with those for oxine, and the effects of structural modification on labelling efficiency has been examined. In order to assess any adverse effects these chelators may have on the functional integrity of platelets, labelling studies have been supplemented with platelet aggregation studies. After establishing the properties which influence the effects of chelators on platelet aggregation, investigations have been undertaken to establish the underlying mechanisms. Aggregation is inhibited by small, bidentate, lipophilic chelators with a high affinity for trivalent cations and has been demonstrated to be consistent with the inhibition of the iron enzyme PGH synthase. Studies in human neutrophils have shown that these chelator properties also enhance inhibition of another iron enzyme, 5- lipoxygenase, and studies performed with purified soybean lipoxygenase have demonstrated for the first time that lipoxygenase inhibition by hydroxypyridinones is associated with the removal of iron from the active site. These properties also favour the uptake of indium-chelator complexes during cell labelling and may therefore be beneficial for identifying compounds which are effective labelling agents but do not cause toxicity by the inhibition of metalloenzymes. Conversely, these studies may be beneficial for those therapeutic uses of metal chelators in which the specific inhibition of metalloenzymes is desirable (e.g. 5-lipoxygenase inhibitors as anti-inflammatory agents, ribonucleotide reductase inhibitors as cell cycle synchronisation agents).

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